Workers exposed to beryllium develop a T cell-dependent immune response directed against a beryllium antigen. A subset of these beryllium sensitized (BeS) subjects progress to chronic beryllium disease (CBD), a granulomatous lung disorder. Our work has shown that a polymorphism in HLA-DPB1 containing a glutamic acid at amino acid position 69 (Glu69), is a risk factor for CBD and BeS. Other genetic susceptibility factors, such as CCR5, TGF-p and glutathione biosynthesis genes appear to affect risk of disease and more severe disease, suggesting that factors which regulate the beryllium specific immune response are important in BeS, and CBD. Besides those listed above, information on other genetic susceptibility factors is limited with a candidate gene approach yielding ambiguous or negative results in studies to date. The relationship between genes and exposure in disease risk is also unclear. The central hypothesis of this study is that immune and other pathogenic susceptibility factors interact with each other and with exposure in the development of BeS and CBD. The central goal of this project is to use a genome wide association (GWA) study to identify genetic regions that confer risk of BeS and CBD.
In Aim 1 we will screen for single nucleotide polymorphisms (SNPs)/genetic regions associated with CBD and BeS compared to controls using the Affymetrix v5.0 array to genotype over 500,000 SNPs. We will control for population stratification in all Aims.
In Aim 2, we will refine the SNPs/regions associated with BeS and CBD in the same population utilizing the lllumina GoldenGate assay. A replication phase for targeted gene exploration will be conducted in Aim 3, utilizing an independent population of CBD, BeS, and control subjects.
In Aim 4 a detailed characterization of approximately 20 genes utilizing all cases and controls will be undertaken, along with assessment of gene-environment interactions. In the largest population studied to date, this Project will link the other projects by defining new genes important in BeS and CBD focusing on those relevant to antigen presentation, relevant to Project 1 and to immune and T cell regulation, relevant to Project 3. It will rely on the Clinical Laboratory Core B for subject recruitment and DNA specimens, and on the Biostatistics and Exposure Core C for analysis and exposure assessment. This study will define promising biomarkers of disease, which when combined with the function/translational aims of Projects 1 and 3, and/or future mechanistic study may result in future therapeutic targets for this disease and other similar diseases. It will also define exposures resulting in BeS and CBD that may have implications for setting new exposure standards, in a disease that serves as a model of environmentally-induced sensitization.

Public Health Relevance

The reason why some workers develop sensitization or disease when exposed to beryllium while others do not, is likely related to genetic and exposure factors, acting in concert to determine disease risk. This study will define genetic and exposure risk factors in CBD, clarifying the exposure-disease relationship. This will have public health implications in understanding of this and other environmental diseases and in the recommendations for exposure reduction to reduce disease risk.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Program Projects (P01)
Project #
5P01ES011810-09
Application #
8382597
Study Section
Special Emphasis Panel (ZES1-TN-J)
Project Start
2012-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
9
Fiscal Year
2012
Total Cost
$423,098
Indirect Cost
Name
University of Colorado Denver
Department
Type
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Fontenot, Andrew P; Falta, Michael T; Kappler, John W et al. (2016) Beryllium-Induced Hypersensitivity: Genetic Susceptibility and Neoantigen Generation. J Immunol 196:22-7
Tooker, Brian C; Ozawa, Katherine; Newman, Lee S (2016) CpG promoter methylation status is not a prognostic indicator of gene expression in beryllium challenge. J Immunotoxicol 13:417-27
Li, Li; Hamzeh, Nabeel; Gillespie, May et al. (2015) Beryllium increases the CD14(dim)CD16+ subset in the lung of chronic beryllium disease. PLoS One 10:e0117276
Tooker, Brian C; Brindley, Stephen M; Chiarappa-Zucca, Marina L et al. (2015) Accelerator mass spectrometry detection of beryllium ions in the antigen processing and presentation pathway. J Immunotoxicol 12:181-7
McKee, A S; Mack, D G; Crawford, F et al. (2015) MyD88 dependence of beryllium-induced dendritic cell trafficking and CD4⁺ T-cell priming. Mucosal Immunol 8:1237-47
Clayton, Gina M; Wang, Yang; Crawford, Frances et al. (2014) Structural basis of chronic beryllium disease: linking allergic hypersensitivity and autoimmunity. Cell 158:132-42
Li, L; Huang, Z; Gillespie, M et al. (2014) p38 Mitogen-Activated Protein Kinase in beryllium-induced dendritic cell activation. Hum Immunol 75:1155-62
Mack, Douglas G; Falta, Michael T; McKee, Amy S et al. (2014) Regulatory T cells modulate granulomatous inflammation in an HLA-DP2 transgenic murine model of beryllium-induced disease. Proc Natl Acad Sci U S A 111:8553-8
Bowerman, Natalie A; Falta, Michael T; Mack, Douglas G et al. (2014) Identification of multiple public TCR repertoires in chronic beryllium disease. J Immunol 192:4571-80

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